ABSTRACT Alzheimer's disease and related dementias (AD/ADRD) have a significant societal impact, yet there are no disease modifying interventions. Root causes of prior clinical trial failures provide instruction for plans to reinvigorate the AD/ADRD therapeutic discovery and development process. Specifically, a diversified portfolio of candidate therapeutic approaches is available based on clinical observations, genetic associations, pathology outcomes and biochemical mechanisms. However, many are neglected in terms of funding and technical pursuit. The prior emphasis on a pathology-based pathway can be avoided by retaining a therapeutic emphasis on discrete but complementary aspects of pathophysiology progression mechanisms. Synaptic dysfunction is one example with diverse potential targets. Synaptic dysfunction underlies subtle amnesic changes occurring prior to the development of the classical histopathologic hallmarks. Deteriorated synaptic strengthening is associated with remodeling of various neurotransmitter systems, including cholinergic, noradrenergic, dopaminergic and serotonergic systems. The serotonergic system is both an underexplored therapeutic mechanism and is especially attractive considering that serotonin is more than a neurotransmitter. Further, clinical findings that 5-hydroxytryptamine receptor 2b (5-HT2bR) expression is increased in AD patient brains and that AD patients respond to a non-selective 5-HT2bR antagonist suggest the potential utility of optimized 5-HT2bR antagonists in AD. We developed a small molecule, MW01-8-071HAB (=MW071), that suppresses LTP defects as well as associative and spatial memory in models of amyloid-beta (A?) and tau elevation. Functional screens for off-target agonist and antagonist activity with 158 known GPCRs demonstrated that MW071 is a selective 5-HT2bR antagonist. Importantly, MW071 lacks 5-HT2BR agonist activity. Avoiding agonist activity is landmark. Approved drugs with 5-HT2bR agonist activity have high risk for cardiac valve toxicity, resulting in withdrawal or black box warnings. Therefore, the promising efficacy in AD relevant models, a pharmacological profile that includes highly selective antagonist activity in the absence of agonist activity, and the availability of a back-up candidate (MW109) adds to the overall appeal of MW071 as a starting point. Our proposed early-stage studies will further de-risk MW071 and MW109 in order to generate and qualify a candidate for a future IND-enabling late stage U01 application: Aim 1. Perform secondary pharmacology analyses following FDA guidance, as a necessary prelude and a firm foundation for future GxP IND-enabling preclinical safety and toxicology research. Aim 2. Validate the efficacy of MW071 and MW109 in prevention/reversal of synaptic and memory impairments in AD-relevant animal models. Quantitative milestones will determine progression through Go/No Go decision points. Successful outcomes and deliverables will allow for future support of GxP IND-enabling evaluation and first-in-human assessment.